Quercetin Attenuates Metabolic Dysfunction and Reshapes Hypothalamic m6A-Related, Leptin–Insulin, and Melanocortin-Associated Transcription in High-Fat-Diet-Fed Rats
- 1Laboratorio de Biología Molecular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
- 2Laboratorio de Farmacología y Medicina Hiperbárica Experimental, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
Abstract
Background/Objectives: High-fat diet (HFD) feeding disrupts systemic metabolism and hypothalamic mechanisms that coordinate energy balance. Whether quercetin modifies coordinated hypothalamic transcription linking m6A-related regulation with leptin–insulin- and melanocortin-associated biology remains unclear. We examined the metabolic and hypothalamic transcriptional response to quercetin during chronic HFD exposure. Methods: Male Wistar rats were studied for 16 weeks in a 2 × 2 factorial design: Control (n = 8), Control + quercetin (n = 5), HFD (n = 5), and HFD + quercetin (n = 6). Quercetin was administered orally at 100 mg/kg/day. Body weight, fasting glucose, food/fluid intake, calculated energy intake, oral glucose tolerance, terminal adiposity, lipids, and a 21-transcript hypothalamic RT-qPCR panel were evaluated. Analyses included factorial models with HC3 inference and FDR control, PCA/PERMANOVA, predefined transcriptional modules, bootstrap and leave-one-sample-out sensitivity analyses, treatment-adjusted covariance, and shrinkage regularization. Results: At week 16, HFD + quercetin reduced glucose AUC relative to HFD by 2415 mg·min/dL (q = 0.0029), visceral fat by 5.16 g (q = 0.004), and triglycerides by 47.03 mg/dL (q < 0.001), without a corresponding difference in final body weight. Diet × quercetin interactions were supported for week-16 AUC, visceral adiposity, triglycerides, and 15 of 21 hypothalamic transcripts. Sixteen of 21 transcripts met robustness criteria for the HFD + quercetin versus HFD contrast. PC1 and PC2 captured 73.5% of transcriptional variance, and all three predefined transcriptional modules showed robust diet-dependent responses. Regularized covariance sensitivity preserved the direction of all 210 treatment-adjusted transcript associations. Conclusions: The principal metabolic effects of quercetin were predominantly evident under HFD conditions and were accompanied by coordinated hypothalamic transcriptional remodeling across m6A-related, leptin–insulin-associated, and melanocortin-associated domains. These data define a transcriptional architecture for mechanistic follow-up without implying direct measurement of circulating leptin or insulin, m6A activity, protein abundance, or pathway activation.
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BibTeX
@article{garciarivero2026quercetin,
title = {{Quercetin Attenuates Metabolic Dysfunction and Reshapes Hypothalamic m6A-Related, Leptin–Insulin, and Melanocortin-Associated Transcription in High-Fat-Diet-Fed Rats}},
author = {Alexis Alejandro García-Rivero and Ángel Miliar-García and Antonio Ávila-Guerrero and María de los Ángeles Martínez-Godínez and María del Carmen Castillo-Hernández and Gustavo Guevara-Balcázar and Aarón Domínguez-López},
journal = {Metabolites},
year = {2026},
month = oct,
doi = {10.3390/metabo16100773},
url = {https://www.mdpi.com/2218-1989/16/10/773},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Quercetin Attenuates Metabolic Dysfunction and Reshapes Hypothalamic m6A-Related, Leptin–Insulin, and Melanocortin-Associated Transcription in High-Fat-Diet-Fed Rats
AU - Alexis Alejandro García-Rivero
AU - Ángel Miliar-García
AU - Antonio Ávila-Guerrero
AU - María de los Ángeles Martínez-Godínez
AU - María del Carmen Castillo-Hernández
AU - Gustavo Guevara-Balcázar
AU - Aarón Domínguez-López
PY - 2026
DA - 2026/10/01
JO - Metabolites
DO - 10.3390/metabo16100773
UR - https://www.mdpi.com/2218-1989/16/10/773
AB - Background/Objectives: High-fat diet (HFD) feeding disrupts systemic metabolism and hypothalamic mechanisms that coordinate energy balance. Whether quercetin modifies coordinated hypothalamic transcription linking m6A-related regulation with leptin–insulin- and melanocortin-associated biology remains unclear. We examined the metabolic and hypothalamic transcriptional response to quercetin during chronic HFD exposure. Methods: Male Wistar rats were studied for 16 weeks in a 2 × 2 factorial design: Control (n = 8), Control + quercetin (n = 5), HFD (n = 5), and HFD + quercetin (n = 6). Quercetin was administered orally at 100 mg/kg/day. Body weight, fasting glucose, food/fluid intake, calculated energy intake, oral glucose tolerance, terminal adiposity, lipids, and a 21-transcript hypothalamic RT-qPCR panel were evaluated. Analyses included factorial models with HC3 inference and FDR control, PCA/PERMANOVA, predefined transcriptional modules, bootstrap and leave-one-sample-out sensitivity analyses, treatment-adjusted covariance, and shrinkage regularization. Results: At week 16, HFD + quercetin reduced glucose AUC relative to HFD by 2415 mg·min/dL (q = 0.0029), visceral fat by 5.16 g (q = 0.004), and triglycerides by 47.03 mg/dL (q < 0.001), without a corresponding difference in final body weight. Diet × quercetin interactions were supported for week-16 AUC, visceral adiposity, triglycerides, and 15 of 21 hypothalamic transcripts. Sixteen of 21 transcripts met robustness criteria for the HFD + quercetin versus HFD contrast. PC1 and PC2 captured 73.5% of transcriptional variance, and all three predefined transcriptional modules showed robust diet-dependent responses. Regularized covariance sensitivity preserved the direction of all 210 treatment-adjusted transcript associations. Conclusions: The principal metabolic effects of quercetin were predominantly evident under HFD conditions and were accompanied by coordinated hypothalamic transcriptional remodeling across m6A-related, leptin–insulin-associated, and melanocortin-associated domains. These data define a transcriptional architecture for mechanistic follow-up without implying direct measurement of circulating leptin or insulin, m6A activity, protein abundance, or pathway activation.
SN - 2218-1989
ER -